Amino alcohol esters of alkyl-substituted alkoxy benzoic acids



Patented Oct. 22,1946

UNITED STATES l PATENT OFFICE AMINO ALCOHOL ESTERS OF ALKYL-SUB- STITUTED ALKOXY BENZOIC ACIDS Walter G. Christiansen, Glen Ridge, and Sidney E. Harris, Nutley, N. J., assignors to E. R. Squibb & Sons, New York, N. Y., a corporation of New York 7 7 No Drawing. Original application September 9 1937, Serial No. 163,034. Divided and this application June 28, 1944,'Serial No. 542,622

(alkyl) wherein R represents a divalent radical providing a continuous carbon bridge, preferably an alkylene radical.

The compounds of this invention are valuable therapeutic agents, being particularly eifective for inducing local anesthesia.

In the practice of this invention, an aracyl halide of the general formula (lower alkyl)CH -O J-(halogen) (alkyl) is reacted with an alcohol of the formula HO-R-N (alkyl) to produce the desired ester.

The amino-esters of the invention are generally recovered in the form of their addition salts with hydrochloric acid. However, other acids forming addition-salts with amines may be used in place of hydrochloric; such acids are boric, nitric, lactic, tartaric, citric, phosphoric, sulfuric, picric, and picrolonic. The addition salts may be converted into the free bases in the usual manner.

The following examples are illustrative of the invention:

EXAMPLE 1 p-diethylamino-ethyl ester of 3-methyl-4-ethorybenzoic acid 13 g. of 3-methyl-4-ethoxy-benzoic acid and 15 g. of phosphorus pentachloride are heated on a steam bath for 30 minutes, and then fractionally distilled in vacuo, the fraction 3-methyl-4- ethoXy-benzoyl chloride being obtained as a colorless liquid boiling at 147-152 C./6 mm. A solution comprising 6.5 g. of this fraction dissolved in 16 cc. of dry benzene is mixed with 7.5 g. of diethylamino-ethanol dissolved in 18 cc. of dry benzene, and the mixture boiled for 60 minutes;

4 Claims. (Cl. 260 473) cooling the reaction mixture causes a white crystalline precipitate of p-diethylamino-ethanol hydrochloride to separate out completely; then filtering, treating the filtrate with alcoholic hydrochloric acid, and distilling off the benzene and alcohol, leaves a white solid residue which upon recrystallization from a mixture of absolute alcohol and dry ether, yields the hydrochloride of the desired product as a white crystalline precipitate having a melting point of 142=.5-l45 0.

EXAMPLE 2 p-diethylammo-ethyl ester of 2-methyl-4-ethoxybenzoic acid 7.5 g. of 2-methyl-4-ethoxy-benzoic acid is warmed with 8.6 g. of phosphorus pentachloride until the reaction ceases; fractional distillation of the reactants under reduced pressure yields 2- methyli-ethoxy-benzoyl chloride as a colorless liquid boiling at Bil- C./3 mm. A solution of 6 g. of this fraction in 20 cc. of dry benzene is treated with 7.6 g. of fl-diethylamino-ethanol dissolved in 10 cc. of dry benzene, and crystals of 'diethylamino-ethanol hydrochloride separate out; filtering off the precipitate, treating the filtrate with alcoholic hydrochloric acid and diluting it with dry ether, yields the hydrochloride of the desired ester as a white crystalline solid melting at 101-103 0.

EXAMPLE 3 Gamma-dimethyZamino-prom Z ester of B-methyl- 4-butomy-benzoic acid EXAMPLE 4.

cam-Di (dimethylamtnomethyl) -gamma-phenyl-npropyl ester of 3-methyl-4-n-butomybenzoic acid (hyd ochloride) 36 g. of the ethyl ester of 3-methyl-4-hydroxybenzoic acid and 27.4 g. of n-butyl bromide dissolved in 200 cc. acetone are treated with 84 g. anhydrous potassium carbonate, and the reaction mixture is then refluxed, with stirring, for 15 hours. The potassium arbonate and potassium bromide precipitated are filtered ofi, the acetone distilled from the filtrate, and the residue boiled with dilute sodium hydroxide solution until dissolved. The product, 3-methyl-4- n-butoxy benzoic acid, is precipitate'dwith hydrogen chloride; and after filtering, washing and dryin the precipitate, and recrystallizing from 60% alcohol, is obtained in the form of white plates melting at 144-116" C. (corrected).

15 g. of this acid is treated with 15 g. phosphorus pentachloride to about 70 C. until hydrogen chloride is no longer evolved, and the reaction mixture is fractionally distilled vacuo. The product, 3-methyl-4-n-butoxy-benzoyl chloride boils at 144-154 C. at 1.5 mm.

1.05 g. of 3-methyl-4-n-butoxy-benzoyl chloride and 1.25 g of m,a-di(dimethylamiiiomethyl)- gamma-phenyl-propanol are dissolved in 10 cc. of chloroform and the solution is refluxed for a few minutes. Dry ether is added until a faint precipitate appears, and the whole is allowed to stand for sometime. The crystalline precipitate formed is filtered off and washed with dry ether; it melts at 161-162 C. (corrected).

EXAMPLE 5 a-Methyl a-dimethylaminomethylm-amyl ester of 3-17;ethyl -n-butozy-benzoic acid (hydrochloride) 4.4 g. of 3-methyl-4-n-butoxy-benzoyl chloride and 3.0 g. of a-methyl-a-dimethylaminomethyln-amyl alcohol are reacted together in cc. of chloroform as directed in Example 4. The product melts at 126-131 C. (corrected).

The following are among the many other compounds embraced by the present invention, and may be prepared according to the directions given above:

4 6. a-methyl-u-dimethylaminomethyl gammaphenyl-n-propyl ester of 3-methyl-4-n-butoxybenzoic acid.

7. -Di-dimethylaminomethyl-n-amy1 ester of 3-methyl-4en-butoxy-benzioc acid. 8. p-Dimethylamino-n-propyl ester of B-methyl-4-propoXy-benz0ic acid.

9. Gamma-oliethylamino-n-propyl ester of 3- ethyl-i-n-propoxy-benzoic acid.

1'0. Dlta-diethylamino-n-buty1 ester of 3- methyll-n-butoxy-benzoic acid.

"The invention may be variously otherwise embodied'within the scope of the appended claims.

We claim: 1 A compound of the group consisting of: aminoeesters of the formula RHF L wherein R represents a divalent alkyl residue with 2 to 4 carbon atoms R represents an alkyl residue with 2 to 4 carbon atoms, R" represents an alkyl residue with 1 to 2 carbon atoms, and 3 represents an alkyl residue with 1 to 2 carbon atoms; and acid-addition salts thereof.

2. The hydrochloride of fl-diethylamino-ethyl 3-methyl-4-eth0Xy-benzoic acid.

3. The hydrochloride of p-diethylamino-ethyl Z-methyll-ethoxy-benzoic acid.

'I h d o l ride o a-me h amino-propyl 3-methyll-n-butoxy-benzoate.

WALTER CHRIYSTIANSEN. SIDNEY E. HARRIS. 

